In the past, orally-disintegrating tablets have been developed as highly convenient forms which can safely be taken by patients who have difficulty in swallowing drugs, elderly people, children, etc. and which can easily be taken without water. It is important that orally-disintegrating tablets have sufficient breaking strength (tablet hardness) such that any cracks, powdering, etc. are not caused in the tablets during production or transportation of the tablets or during breaking the seals in the same manner as general tablets, and also, it is important that orally-disintegrating tablets have excellent disintegrability (disintegration time) such that the tablets immediately disintegrate in the oral cavity.
The tablet hardness and disintegrability are mutually opposing properties. In general, when a molding pressure is increased to increase the hardness, the disintegration time tends to be prolonged, and, when the molding pressure is reduced to shorten the disintegration time, the hardness tends to be smaller. Therefore, various technologies have been developed in order to cope with both the two properties or to achieve an optimal balance between the two properties.
Furthermore, components of the particles, granulation methods, etc. have been studied in order to impart superior moldability to particles or particulate compositions constituting tablets.
Additionally, an acid-type carboxymethylcellulose is a cellulose derivative otherwise called “carmellose”, and this substance has properties that, when water is added to the substance, the substance swells but converts into a suspension having almost no viscosity. Therefore, an acid-type carboxymethylcellulose has been used as an ingredient for orally-disintegrating tablets, namely as a base, binder, excipient or disintegrator therefor.
Also, a crystalline cellulose is a white water-insoluble powdery substance obtained by partially depolymerizing α-cellulose, which is obtained from fibrous plants, with acids, followed by purification. A crystalline cellulose has no taste, and, since the substance is chemically inactive, it does not change even when being mixed with medicaments. Therefore, a crystalline cellulose has been used for purposes of a pharmaceutical additive, in particular, an excipient, binder, disintegrator or the like for preparing tablets. In addition, a crystalline cellulose has been used as an emulsification stabilizer or the like for cosmetics, dairy products, etc. besides an additive for pharmaceuticals.
For example, PTL 1 describes a disintegrative particulate composition which is produced through homogeneous dispersion of mannitol, xylitol, an inorganic excipient, a disintegrator and carmellose in the presence of water, followed by drying the dispersion. The composition is characterized in that composite particles including xylitol dispersed in mannitol particles in the solid state are formed, and that the inorganic excipient, the disintegrator and carmellose are dispersed in the composite particles. The disintegrative particulate composition is produced through spray granulation of a dispersion obtained by dispersing these components in an aqueous medium, or is produced by spraying the dispersion to carriers such as of mannitol.
Although crospovidone and crystalline cellulose and the like are described as the disintegrator in PTL 1, there is no specific example of a disintegrative particulate composition that simultaneously comprises both crospovidone and crystalline cellulose. PTL 1 also discloses that the inorganic excipient has a function of controlling water-concentration in the tablet to reduce the water content so that it will promote the reduction of a binding force at joining points between the disintegrative particle compositions. Thus, the inorganic excipient is an essential component for obtaining an excellent disintegrability in the invention disclosed in PTL 1.
Furthermore, it is also an essential requirement that mannitol and xylitol comprised in the integrative particulate composition have to form the “composite particles” having the above-mentioned particular structure.
Also, PTL 2 describes an orally-disintegrating tablet which contains an active ingredient and 10% (w/w) or more of carboxymethylcellulose relative to the total amount. The components are mixed, and then, the orally-disintegrating tablet is prepared with a tablet machine.
Moreover, PTL 3 describes a method of producing an orally-disintegrating tablet which contains loratadine as a medicinal ingredient. This production method is characterized in that two-stage granulation steps are carried out therein, i.e. loratadine and at least one type of an additive such as a binder, excipient, or disintegrator are granulated in the first granulation step, and, in the second granulation step, granules obtained in the first granulation step are further granulated together with at least one type of the same additive such as a binder, excipient, or disintegrator as that used in the first granulation step. As one example of the disintegrator, carmellose is mentioned therein.
Furthermore, PTL 4 describes a method of producing an orally-disintegrating tablet. The production method includes a step of spraying a water suspension of a water-soluble but hydrophilic disintegrating component onto a mixture of an excipient and a medicament to obtain granules A including the medicament; a step of spraying the same water suspension of the disintegrating component onto the excipient to obtain granules B not including the medicament; and a step of subjecting the resulting granules A and B to compression molding.